Most drugs which humans abuse serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals. Experiments are being conducted to assess neuropharmacological and behavioral mechanisms underlying drug-seeking and drug-taking behavior in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. Currently, studies are focusing on cocaine, nicotine and methamphetamine. One series of studies sought to determine the neurobiological correlates of methamphetamine self-administration. A "yoked" procedure was utilized in which rats were trained simultaneously in groups of three, with two rats serving as yoked controls which received an injection of 0.1 mg/kg methamphetamine or saline each time the third rat self-administered 0.1 mg/kg methamphetamine. Twenty-four hours following the last injections, rats that self-administered methamphetamine showed marked decreases in somatodendritic D2 autoreceptors in the ventral tegmental area and the medial and dorsal part of the substantia nigra zona compacta with a corresponding down-regulation of D1 receptors in the shell of the nucleus accumbens. These changes were not observed in either the yoked methamphetamine or saline groups. These data show that neurobiological changes following methamphetamine self-administration are not due solely to the pharmacological properties of the drug, but are dependent on active drug self-administration. Another series of experiments focused on serotonergic modulation of methamphetamine self-administration. We have found that serotonin release induced by fenfluramine treatment markedly decreases methamphetamine self-administration. Dopamine release induced by phentermine treatment also decreases methamphetamine self-administration, but to a lesser extent. This suggests that modulation of serotonergic neurotransmitter systems might be effective in the treatment of methamphetamine abuse. Finally, we are continuing our studies on combining stimuli associated with drug administration. Previous studies have shown that combining stimuli associated with cocaine self-administration leads to an increase in both drug-seeking and drug-taking. Recent studies have expanded on the finding by showing that a similar phenomenon also occurs for the classically conditioned effects of cocaine. Thus, cocaine functions similarly to non-drug reinforcers in this regard. These studies also show that combining stimuli associated with cocaine can be expected to potentiate any conditioned effects.